Innate immunity in alcoholic liver disease

Excessive alcohol consumption is a leading cause of chronic liver disease in the Western world. Alcohol-induced hepatotoxicity and oxidative stress are important mechanisms contributing to the pathogenesis of alcoholic liver disease. However, emerging evidence suggests that activation of innate immunity involving TLR4 and complement also plays an important role in initiating alcoholic steatohepatitis and fibrosis, but the role of adaptive immunity in the pathogenesis of alcoholic liver disease remains obscure. Activation of a TLR4-mediated MyD88-independent (TRIF/IRF-3) signaling pathway in Kupffer cells contributes to alcoholic steatohepatitis, whereas activation of TLR4 signaling in hepatic stellate cells promotes liver fibrosis. Alcohol consumption activates the complement system in the liver by yet unidentified mechanisms, leading to alcoholic steatohepatitis. In contrast to activation of TLR4 and complement, alcohol consumption can inhibit natural killer cells, another important innate immunity component, contributing to alcohol-mediated acceleration of viral infection and liver fibrosis in patients with chronic viral hepatitis. Understanding of the role of innate immunity in the pathogenesis of alcoholic liver disease may help us identify novel therapeutic targets to treat this disease.     

Role of IRAK-M in Alcohol Induced Liver Injury

Increasing evidence suggests that innate immunity plays an important role in alcohol-induced liver injury and most studies have focused on positive regulation of innate immunity. The main objective of this study was to investigate the negative regulator of innate immunity, IL-1/Toll-like receptor (TLR) signaling pathways and interleukin receptor-associated kinase-M (IRAK-M) in alcoholic liver injury. We established an alcohol-induced liver injury model using wild type and IRAK-M deficient B6 mice and investigated the possible mechanisms. We found that in the absence of IRAK-M, liver damage by alcohol was worse with higher alanine transaminase (ALT), more immune cell infiltration and increased numbers of IFNγ producing cells. We also found enhanced phagocytic activity in CD68⁺ cells. Moreover, our results revealed altered gut bacteria after alcohol consumption and this was more striking in the absence of IRAK-M. Our study provides evidence that IRAK-M plays an important role in alcohol-induced liver injury and IRAK-M negatively regulates the innate and possibly the adaptive immune response in the liver reacting to acute insult by alcohol. In the absence of IRAK-M, the hosts developed worse liver injury, enhanced gut permeability and altered gut microbiota.     

The role of lipins in innate immunity and inflammation

Lipins are phosphatidic acid phosphatase enzymes whose cellular function in regulating lipid metabolism has been known for decades, particularly in metabolically active tissues such as adipose tissue or liver. In recent years evidence is accumulating for key regulatory roles of the lipin family in innate immune cells. Lipins may help regulate signaling through relevant immune receptors such as Toll-like receptors, and are also integral part of the cellular machinery for lipid storage in these cells, thereby modulating certain inflammatory processes. Mutations in genes that encode for members of this family produce autoinflammatory hereditary diseases or diseases with an important inflammatory component in humans. In this review we summarize recent findings on the role of lipins in cells of the innate immune system and in the onset and progress of inflammatory processes.     

GammadeltaT cells initiate acute inflammation and injury in adenovirus-infected liver via cytokine-chemokine cross talk

Emerging studies suggest an important role for the innate immune response in replication-defective adenovirus (Ad)-mediated acute liver toxicity. Specifically, classical innate immune cells (including NK cells, neutrophils, and Kupffer cells) have all been implicated in the development of Ad-mediated acute liver toxicity. The nonclassical innate immune T cell, the gammadeltaT cell, has been implicated in the pathophysiology of several viral infections that predominantly affect the mucosa and brain, but the specific role in the pathology of AdLacZ-mediated acute liver inflammation and injury as well as accompanying vector clearance is largely unknown. In the present study, we demonstrated that a CXCL9-CXCR3-dependent mechanism governed the accumulation of gammadeltaT cells in the livers of mice infected with Ad expressing the Escherichia coli LacZ gene (AdLacZ). We also showed a critical role for gammadeltaT cells in initiating acute liver toxicity after AdLacZ administration, driven in part by the ability of gammadeltaT cells to promote the recruitment of the conventional T cell, the CD8(+) T cell, into the liver. Furthermore, reduced hepatic injury in AdLacZ-infected gammadeltaT-cell-deficient mice was associated with lower hepatic levels of gamma interferon (IFN-gamma) and CXCL9, an IFN-gamma-inducible chemokine. Finally, our study highlighted a key role for IFN-gamma and CXCL9 cross talk acting in a feedback loop to drive the proinflammatory effects of gammadeltaT cells during AdLacZ-mediated acute liver toxicity. Specifically, intracellular IFN-gamma produced by activated hepatic gammadeltaT cells interacts with hepatocytes to mediate hepatic CXCL9 production, with the consequent accumulation of CXCR3-bearing gammadeltaT cells in the liver to cause acute liver damage without vector clearance.     

肝脏固有免疫系统对肠源性感染的免疫应答与免疫耐受机制

肝特殊的解剖结构及生理特征使其成为暴露肠源性抗原的主要器官。由于肝具有独特的固有免疫系统,在正常情况下,肝分布多种致耐受的抗原提呈细胞,对持续性表达或递呈于肝的肠源性抗原物质,诱发针对该抗原的系统性免疫耐受,避免肝受到不必要的免疫损伤。当炎症发生及肝脏固有免疫系统活化时,则通过免疫效应细胞及免疫效应因子对肠源性病原体发挥强烈地免疫应答以控制感染。该过程形成机制的研究对肝功能的理解及肝性疾病的预防与治疗至关重要。本文就肝固有免疫系统对肠源性感染的免疫应答与免疫耐受形成机制作一综述。     

TLR-4 regulates CD8+ T cell trapping in the liver

Mammalian TLRs are understood primarily as an activating system for innate and adaptive immunity, but have also been implicated in sensing cellular damage and in promoting intestinal integrity. In this study we show that TLR-4 also controls the in vivo distribution of activated CD8+ T cells. The liver is a site for trapping and apoptosis of activated CD8+ T cells during systemic immune responses, but the reason for this is unknown. In this study we tested the hypothesis that the liver's constant exposure to endotoxin, derived from commensal bacteria in the gut, acts via TLR-4 to promote activated T cell adhesion. In the absence of TLR-4, the liver was compromised in its ability to sequester activated CD8+ T cells, and there was an inverse correlation between the frequency of activated CD8+ T cells trapped in the liver and their frequency in the circulating pool. Thus, in the absence of any inflammation, TLR-4 ligands play a significant role in the ability of the liver to trap activated CD8+ T cells. This provides a new perspective on the regulation of immune responses by TLR-4 under basal conditions.     

Tissue-resident natural killer cells in the livers

Nature killer(NK) cells are important lymphocytes of the innate immune system,well known for their pivotal roles in immune surveillance and defense against tumor and virus-infected cells.Current studies have revealed that NK cells are not a homogeneous population,but instead consist of distinct subsets with diverse characteristics.As an organ with predominant innate immunity,the liver is enriched with NK cells,among which two distinct NK cell subsets have recently been identified:conventional NK(cNK)cells and tissue-resident NK(trNK) cells.Liver trNK cells are markedly different from cNK cells in many aspects,representing a new lineage of innate lymphoid cell(ILC) family.Here,we summarize the phenotypic and functional features of liver trNK cells,and review current knowledge regarding developmental pathway of liver trNK cells.We also overview recent advances in human liver trNK cells and discuss the striking shared hallmarks of trNK cells in different tissues.     

自然杀伤细胞参与肝脏恶性肿瘤免疫逃逸研究进展

自然杀伤细胞是机体固有免疫系统重要组成部分,在肝脏等免疫器官中含量丰富,而且免疫表型、功能等表现出器官特异性。在正常情况下,靶细胞表面的配体与自然杀伤细胞表面的活化性受体直接结合并释放细胞毒性物质,诱导活化靶细胞凋亡程序,从而发挥抗感染、抗肿瘤作用。然而肿瘤细胞仍能够通过多种途径逃逸机体的免疫监视功能,研究认为肿瘤细胞抗原异常表达、肿瘤微环境中细胞因子及其他免疫细胞相互作用等因素所引起的自然杀伤细胞活性降低对于诱导肿瘤免疫逃逸起重要作用。本文综述了自然杀伤细胞在肝脏恶性肿瘤发生过程中参与免疫逃逸的机制及研究进展,以期为临床抗肿瘤免疫治疗的研究提供参考。     

NK cells in liver homeostasis and viral hepatitis

As an important member of the innate immune system, natural killer (NK) cells are well known for their rapid and efficient immune responses against infectious agents and tumors. NK cells are widely distributed throughout the body and are particularly enriched within the liver, where they display unique phenotypic and functional properties, playing important roles in various liver diseases. Herein, we present an overview of liver NK cell properties with regard to phenotype, function, and subset composition at steady state, and we also summarize the complex reciprocal interactions between liver NK cells and other cell types within the local environment of the liver. We also provide an overview of recent advances demonstrating the roles of NK cells in viral hepatitis, including a discussion of NK cell altered states and their beneficial versus harmful effects during hepatitis B virus and hepatitis C virus infection.     

Natural killer cells and autoimmunity

Autoimmune diseases are often characterized as clinical syndromes caused by the inappropriate activation of T or B cells resulting in systemic or organ-specific damage. However, studies support a role for the innate immune system, and in particular natural killer (NK) cells, in stimulating or suppressing autoimmunity. This review focuses on recent research elucidating a potential immunoregulatory role for NK cells in modulating T and B cell-mediated autoimmunity.     

Natural killer cells and autoimmunity

Autoimmune diseases are often characterized as clinical syndromes caused by the inappropriate activation of T or B cells resulting in systemic or organ-specific damage. However, studies support a role for the innate immune system, and in particular natural killer (NK) cells, in stimulating or suppressing autoimmunity. This review focuses on recent research elucidating a potential immunoregulatory role for NK cells in modulating T and B cell-mediated autoimmunity.     

Recent insights into the role of the innate immune system in the development of alcoholic liver disease

The innate immune system is responsible for the rapid, initial response of the organism to potentially dangerous stresses, including pathogens, tissue injury, and malignancy. Pattern-recognition receptors of the toll-like receptor (TLR) family expressed by macrophages provide a first line of defense against microbial invasion. Activation of these receptors results in a stimulus-specific expression of genes required to control the infection, including the production of inflammatory cytokines and chemokines, followed by the recruitment of neutrophils to the site of infection. The early stages in the development of alcoholic liver disease (ALD) follow a pattern characteristic of an innate immune response. Kupffer cells, the resident macrophages in the liver, are activated in response to bacterial endotoxins (lipopolysaccharide, LPS), leading to the production of inflammatory and fibrogenic cytokines, reactive oxygen species, as well as the recruitment of neutrophils to the liver. One mechanism by which chronic ethanol can turn the highly regulated innate immune response into a pathway of disease is by disrupting the signal transduction cascades mediating the innate immune response. Recent studies have identified specific modules in the TLR-4 signaling cascade that are disrupted after chronic ethanol exposure, including CD14 and the mitogen-activated protein kinase family members, ERK1/2 and p38. Enhanced activation of these TLR-4 dependent signaling pathways after chronic ethanol likely contributes to the development of alcoholic liver disease.     

Innate recognition of malarial parasites by mammalian hosts

Innate immunity plays a central role in combating infections. However, the importance of innate immune sensors in detecting intracellular parasites, such as Plasmodium spp., has only recently emerged as a central topic in the field of host-pathogen interactions. Genetic dissection of innate immune pathways has uncovered a complex relationship between the host innate immune system and Plasmodium blood-stage parasites. In fact, recognition molecules of the innate immune system, such as toll-like receptors, might not only be implicated in host defense but also in the pathogenesis of the disease. Whether Plasmodium liver stage parasites are recognised and controlled by the host innate immune system remains to be discovered. In this review we discuss recent findings on how the host innate immune system may sense and fight the different forms of Plasmodium and how the latter may have evolved mechanisms to escape host detection and/or to manipulate the defensive reaction of the host.     

Antigen-presenting cell function in the tolerogenic liver environment

The demands that are imposed on the liver as a result of its function as a metabolic organ that extracts nutrients and clears gut-derived microbial products from the blood are met by a unique microanatomical and immunological environment. The inherent tolerogenicity of the liver and its role in the regulation of innate and adaptive immunity are mediated by parenchymal and non-parenchymal antigen-presenting cells (APCs), cell-autonomous molecular pathways and locally produced factors. Here, we review the central role of liver APCs in the regulation of hepatic immune function and also consider how recent insights may be applied in strategies to target liver tolerance for disease therapy.     

Role of myeloid cells in tumor angiogenesis and growth

Cells of the innate immune system have a key role in maintaining homeostasis by providing the first line of defense against many pathogens. Innate immunity can also modulate the activity of acquired immunity by several mechanisms. However, subsets of myeloid cells can facilitate tumor growth, because these cells produce angiogenic factors and can also prevent the immune system from attacking tumor cells. Recent studies also emphasize the role of myeloid cells in mediating refractoriness to anti-VEGF treatments. This function of myeloid cells occurs through a proangiogenic pathway that is, at least in part, driven by the secreted protein Bv8. This review summarizes recent findings on the complex role of bone marrow-derived cells in tumor growth.     

TNFα-Mediated Liver Destruction by Kupffer Cells and Ly6Chi Monocytes during Entamoeba histolytica Infection

Amebic liver abscess (ALA) is a focal destruction of liver tissue due to infection by the protozoan parasite Entamoeba histolytica (E. histolytica). Host tissue damage is attributed mainly to parasite pathogenicity factors, but massive early accumulation of mononuclear cells, including neutrophils, inflammatory monocytes and macrophages, at the site of infection raises the question of whether these cells also contribute to tissue damage. Using highly selective depletion strategies and cell-specific knockout mice, the relative contribution of innate immune cell populations to liver destruction during amebic infection was investigated. Neutrophils were not required for amebic infection nor did they appear to be substantially involved in tissue damage. In contrast, Kupffer cells and inflammatory monocytes contributed substantially to liver destruction during ALA, and tissue damage was mediated primarily by TNFα. These data indicate that besides direct antiparasitic drugs, modulating innate immune responses may potentially be beneficial in limiting ALA pathogenesis.     

Role and function of macrophages in the metabolic syndrome

Macrophages are key innate immune effector cells best known for their role as professional phagocytes, which also include neutrophils and dendritic cells. Recent evidence indicates that macrophages are also key players in metabolic homoeostasis. Macrophages can be found in many tissues, where they respond to metabolic cues and produce pro- and/or anti-inflammatory mediators to modulate metabolite programmes. Certain metabolites, such as fatty acids, ceramides and cholesterol crystals, elicit inflammatory responses through pathogen-sensing signalling pathways, implicating a maladaptation of macrophages and the innate immune system to elevated metabolic stress associated with overnutrition in modern societies. The outcome of this maladaptation is a feedforward inflammatory response leading to a state of unresolved inflammation and a collection of metabolic pathologies, including insulin resistance, fatty liver, atherosclerosis and dyslipidaemia. The present review summarizes what is known about the contributions of macrophages to metabolic diseases and the signalling pathways that are involved in metabolic stress-induced macrophage activation. Understanding the role of macrophages in these processes will help us to develop therapies against detrimental effects of the metabolic syndrome.     

Drosophila innate immune response pathways moonlight in neurodegeneration

In this Extra View, we highlight recent Drosophila research that has uncovered a new role for the innate immune response. The research indicates that, in addition to combating infection, the innate immune response promotes neurodegeneration. Our publication (Petersen et al., 2012) reveals a correlative relationship between the innate immune response and neurodegeneration in a model of the human disease Ataxia-telangiectasia (A-T). We also found that glial cells are responsible for the innate immune response in the A-T model, and work by others implicates glial cells in neurodegeneration. Additionally, publications by Chinchore et al. (2012) and Tan et al. (2008) reveal a causative role for the innate immune response in models of human retinal degenerative disorders and Alzheimer disease, respectively. Collectively, these findings suggest that activation of the innate immune response is a shared cause of neurodegeneration in different human diseases.     

The innate immune system in allograft rejection and tolerance

As T cells alone are both necessary and sufficient for the rejection of virtually all allogeneic tissues, much of transplantation immunology has focused on cells of the adaptive immune system. During the past decade, advances in our understanding of innate responses to pathogen-associated molecules have spurred a "rediscovery" of innate immunity. Fueled by this, an increasing body of literature has emerged in which the role of the innate immune system in allograft rejection and tolerance has been examined more closely. This review will give an overview of recent studies and emerging concepts of how the cellular components of the innate immune system participate in the immune response to solid organ transplantation. These important studies highlight the complex interplay between diverse cells of the immune response and provide the basis for optimal strategies of tolerance induction.